The present invention relates to a pyrrolo[1,2-a]pyrazine derivative effective for inhibiting sPLA2-mediated fatty acid release.
sPLA2 (secretory phospholipase A2) is an enzyme that hydrolyzes membrane phospholipids and has been considered to be a rate-determining enzyme that governs the so-called arachidonate cascade where arachidonic acid, the hydrolysis product, is the starting material. Moreover, lysophospholipids that are produced as by-products in the hydrolysis of phospholipids have been known as important mediators in cardiovascular diseases. Accordingly, in order to normalize excess functions of the arachidonate cascade and the lysophospholipids, it is important to develop compounds which inhibit the liberation of sPLA2-mediated fatty acids (for example, arachidonic acid), namely, compounds which inhibit the activity or production of sPLA2. Such compounds are useful for general treatment of symptoms, which are induced and/or sustained by an excess formation of sPLA2, such as septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arteriosclerosis, cerebral apoplexy, cerebral infarction, inflammatory colitis, psoriasis, cardiac insufficiency, cardiac infarction, and so on. The participation of sPLA2 is considered to be extremely wide and, besides, its action is potent.
There are known, as examples of sPLA2 inhibitor, indole derivatives in EP-620214 (JP Laid-Open No. 010838/95), EP-620215 (JP Laid-Open No. 025850/95), EP-675110 (JP Laid-Open No. 285933/95), WO 96/03376, and WO 99/00360; indene derivatives in WO 96/03120; indolizine derivatives in WO 96/03383; naphthalene derivatives in WO 97/21664 and WO 97/21716; tricyclic derivatives in WO 98/18464; pyrazole derivatives in WO 98/24437; phenylacetamide derivatives in WO 98/24756; phenyl glyoxamide derivatives in WO 98/24794; pyrrole derivatives in WO 98/25609.
The present invention provides pyrrolo[1,2-a]pyrazine derivatives having sPLA2 inhibiting activity and being useful for treatment of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, psoriasis, cardiac failure, and cardiac infarction.
The present invention relates to a compound represented by the formula (I): 
wherein R1 is hydrogen atom or a group selected from (a) C6 to C20 alkyl, C6 to C20 alkenyl, C6 to C20 alkynyl, carbocyclic groups, and heterocyclic groups, (b) the groups represented by (a) each substituted independently with at least one group selected from non-interfering substituents, and (c) xe2x80x94(L1)xe2x80x94R6 wherein L1 is a divalent linking group of 1 to 18 atom(s) selected from hydrogen atom(s), nitrogen atom(s), carbon atom(s), oxygen atom(s), and sulfur atom(s), and R6 is a group selected from the groups (a) and (b);
R2 is hydrogen atom, or a group containing 1 to 4 non-hydrogen atoms;
R3 is xe2x80x94(L2)xe2x80x94(acidic group) wherein L2 is an acid linker having an acid linker length of 1 to 5;
R4 and R5 are selected independently from hydrogen atom, non-interfering substituents, carbocyclic groups, carbocyclic groups substituted with a non-interfering substituent(s), heterocyclic groups, and heterocyclic groups substituted by a non-interfering substituent(s); and
RA is a group represented by the formula: 
wherein L7 is a divalent linker group selected from a bond or a divalent group selected from xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, or xe2x80x94COxe2x80x94, R27 and R28 are independently hydrogen atom, C1 to C3 alkyl or a halogen; X and Y are independently an oxygen atom or a sulfur atom; and Z is xe2x80x94NH2 or xe2x80x94NHNH2; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
Preferred subclass of compounds of formula (I) are those where for R1 is the divalent linking group xe2x80x94(L1)xe2x80x94 is a group represented by any one of the following formula (Ia) or (Ib) or (Ic): 
wherein Q1 is a bond or any one of the divalent groups (Ia) or (Ib) and each R36 is independently hydrogen atom, C1 to C8 alkyl, C1 to C8 haloalkyl, or C1 to C8 alkyloxy. Particularly preferred as the linking group xe2x80x94(L1)xe2x80x94 of R1 is an alkylene chain of 1 or 2 carbon atoms, namely, xe2x80x94(CH2)xe2x80x94 or xe2x80x94(CH2CH2)xe2x80x94.
Preferred sPLA2 inhibitor compounds of the invention are those represented by the formula (II): 
wherein R7 is hydrogen atom or xe2x80x94(CH2)mxe2x80x94R12 wherein m is an integer from 1 to 6, and R12 is (d) a group represented by the formula: 
wherein a, c, e, n, q, and t are independently an integer from 0 to 2, R13 and R14 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, xcex1 is an oxygen atom or a sulfur atom, L5 is xe2x80x94(CH2)vxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2, xcex2 is xe2x80x94CH2xe2x80x94 or xe2x80x94(CH2)2xe2x80x94, xcex3 is an oxygen atom or a sulfur atom, b is an integer from 0 to 3, d is an integer from 0 to 4, f, p, and w are independently an integer from 0 to 5, g is an integer from 0 to 2, r is an integer from 0 to 7, and u is an integer from 0 to 4, or is (e) a member of (d) substituted with at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 haloalkyloxy, C1 to C6 haloalkyl, aryl, and a halogen;
R8 is C1 to C3 alkyl, C1 to C3 alkenyl, C3 to C4 cycloalkyl, C3 to C4 cycloalkenyl, C1 to C2 haloalkyl, C1 to C3 alkyloxy, or C1 to C3 alkylthio;
R9 is xe2x80x94(L3)xe2x80x94R15 wherein L3 is represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R24)xe2x80x94, or xe2x80x94Sxe2x80x94, R16 and R17 are independently hydrogen atom, C1 to C10 alkyl, aryl, aralkyl, alkyloxy, haloalkyl, carboxy, or a halogen, and R24 is hydrogen atom or C1 to C6 alkyl, and R15 is represented by the formula: 
wherein R18 is hydrogen atom, a metal, or C1 to C10 alkyl, R19 is independently hydrogen atom, or C1 to C10 alkyl, and t is an integer from 1 to 8;
R10 and R11 are independently hydrogen atom or a non-interfering substituent selected from hydrogen, C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkenyl, C7 to C12 aralkyl, C7 to C12 alkaryl, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenyl, C1 to C8 alkyloxy, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C2 to C12 alkyloxyalkyl, C2 to C12 alkyloxyalkyloxy, C2 to C12 alkylcarbonyl, C2 to C12 alkylcarbonylamino, C2 to C12 alkyloxyamino, C2 to C12 alkyloxyaminocarbonyl, C1 to C12 alkylamino, C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl, C1 to C8 alkylsulfinyl, C1 to C8 alkylsulfonyl, C2 to C8 haloalkyloxy, C1 to C8 haloalkylsulfonyl, C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl, xe2x80x94C(O)O(C1 to C8 alkyl), xe2x80x94(CH2)zxe2x80x94Oxe2x80x94(C1 to C8 alkyl), benzyloxy, aryloxy, arylthio, xe2x80x94(CONHSO2R25), xe2x80x94CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkoxy, xe2x80x94(CH2)zxe2x80x94CO2H, cyano, cyanoguanidinyl, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, xe2x80x94SO3H, thioacetal, thiocarbonyl, or carbonyl, R25 is C1 to C6 alkyl or aryl, z is an integer from 1 to 8; and RB is a group represented by the formula: 
wherein Z is the same as defined above; the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
The invention also relates to preferred compounds represented by formula (I) or (II) the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates, wherein said R1 and R7 are represented by the formula: 
wherein R13, R14, b, d, f, g, p, r, u, w, xcex1, xcex2, and xcex3 are the same as defined above, L6 is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
The invention also relates to preferred compounds represented by formula (I) and (II), the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates, wherein for the formula (I) and (II) respectively the substituent R2 or R8 is selected from C1 to C3 alkyl or C3 to C4 cycloalkyl.
The invention also relates to a preferred compound of formula (I) or (II), the prodrugs thereof or their pharmaceutically acceptable salts, or their solvates, wherein the L2 and L3 are xe2x80x94Oxe2x80x94CH2xe2x80x94.
The invention also relates to a preferred compound represented by the formula (III): 
wherein R20 is a group represented by the formula: 
wherein L6, R13 R14, b, d, f, g, p, r, u, w, xcex1, xcex2 and xcex3 are the same as defined above;
R21 is C1 to C3 alkyl or C3 to C4 cycloalkyl;
L4 is xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94N(R24)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Oxe2x80x94CH((CH2)2Ph)xe2x80x94 wherein R24 is hydrogen atom or C1 to C6 alkyl and Ph is phenyl;
R22 is xe2x80x94COOH, xe2x80x94SO3H, or P(O)(OH)2;
R23 is hydrogen atom, C1 to C6 alkyl, C7 to C12 aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogen, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, arylthio, a carbocyclic group, or a heterocyclic group; and RB is the same as defined above; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
The invention also relates to most preferred compounds represented by the formula (IV): 
wherein R20, R21, R23, and RB are the same as defined above; and k is an integer from 1 to 3; the prodrugs thereof; or their pharmaceutically acceptable salts; or their solvates.
The invention also relates to a preferred compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in formula (III) wherein L4 is xe2x80x94Oxe2x80x94CH2xe2x80x94.
The invention further relates to a preferred compound, the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates as described in formula (I), (II), (III), or (IV), wherein RA and RB are xe2x80x94COCONH2xe2x80x94.
The invention also relates to preferred compounds formula (I), (II), (III), or (IV), the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates wherein RA and RB are xe2x80x94CH2CONH2xe2x80x94.
The invention further relates to preferred compounds of formula (I), (II), (III), or (IV), the prodrugs thereof, or their pharmaceutically acceptable salts, or their solvates wherein RA and RB are xe2x80x94CH2CONHNH2xe2x80x94.
The invention also relates to preferred compounds of formula (I), (II), (III), or (IV) in the form of ester type prodrug.
The invention further relates to specific preferred sPLA2 inhibitor compounds of formula (I), (II), (III), or (IV), namely, a pyrrolo[1,2-a]pyrazine compound selected from the group consisting of:
[6-Benzyl-7-ethyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[6-Cyclohexylmethyl-7-ethyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1-yl]oxyacetic acid,
[7-Ethyl-6-(3-methoxybenzyl)-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[6-(Benzo[b]thiophen-6-ylmethyl)-7-ethyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1-yl]oxyacetic acid,
[6-Benzyl-7-ethyl-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[7-Ethyl-6-(4-fluorobenzyl)-3-methyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1-yl]oxyacetic acid,
[6-(2-Biphenylmethyl)-7-ethyl-3-methyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1-yl]oxyacetic acid,
[6-Cyclopentylmethyl-7-ethyl-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[6-(2-Benzyl)benzyl-7-ethyl-3-methyl-8-oxamoylpyrrolo [1,2-a]pyrazin- 1 -yl]oxyacetic acid,
[7-Ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[7-Ethyl-6-(3-fluorobenzyl)-3-methyl-8-oxamoylpyrrolo [1 ,2-a]pyrazin-1 -yl]oxyacetic acid,
[6-Benzyl-7-ethyl-3-isopropyl-8-oxamoylpyrrolo [1,2-a]pyrazin- 1-yl]oxyacetic acid,
[6-Benzyl-3,7-diethyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1-yloxyacetic acid,
[6-Benzyl-7-ethyl-8-oxamoyl-3-phenylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[6-Benzyl-7-ethyl-3-isobutyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[3,6-Dibenzyl-7-ethyl-8-oxamoylpyrrolo[1,2-a]pyrazin- 1-yl]oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6-(2-(2-thienyl)benzyl)pyrrolo[1,2-a]pyrazin- 1 -yl]oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6-(2-phenylethynylbenzyl)pyrrolo [1,2-a]pyrazin- 1-yl]oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6-(2-phenyloxybenzyl) pyrrolo [1,2-a]pyrazin-1-yl]oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6-(2-(3-thienyl)benzyl)pyrrolo [1,2-a]pyrazin- 1 -yl]oxyacetic acid,
[7-Ethyl-3-methyl-6-(2-(5-methylthien-2-yl)benzyl)-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetic acid,
[7-Ethyl-6-(2-(4-methoxyphenyl)benzyl)-3-methyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1-yl ]oxyacetic acid,
[7-Ethyl-3-methyl-6-(2-(4-methylphenyl)benzyl)-8-oxamoylpyrrolo[ 1,2-a]pyrazin- 1-yl]oxyacetic acid,
[7-Ethyl-3-methyl-8-oxamoyl-6-(2-(2-phenylethyl)benzyl)pyrrolo[1,2-a]pyrazin- 1 -yl]oxyacetic acid,
[6-Benzyl-7-cyclopropyl-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin- 1 -ylloxyacetic acid,
[7xe2x80x94Cyclopropyl-6-(4-fluorobenzyl)-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin- 1 -yl]oxyacetic acid,
[6-Benzyl-3-cyclohexyl-7-ethyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1 -yl]oxyacetic acid,
[6-(2-Biphenylmethyl)-3-cyclohexyl-7-ethyl-8-oxamoylpyrrolo[1,2-a]pyrazin- 1-yl]oxyacetic acid,
[6-Benzyl-3,7-dimethyl-8-oxamoylpyrrolo [ 1,2-a]pyrazin-1-ylloxyacetic acid,
[7-Ethyl-3-methyl-6-(5-methylthien-2-ylmethyl)-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl ]oxyacetic acid,
[6-(Benzo[b]thiophen-3-ylmethyl)-7-ethyl-3-methyl-8-oxamoylpyrrolo [1,2-a]pyrazin- 1-yl ]oxyacetic acid,
Sodium [7-ethyl-6-(4-fluorobenzyl)-3-methyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1-yl]oxyacetate,
Sodium [7-ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1 -yl]oxyacetate,
Sodium [7-ethyl-3-methyl-8-oxamoyl-6-(2-(2-thienyl)benzyl)pyrrolo[1,2-a]pyrazin-1-yl ]oxyacetate,
Sodium [7-ethyl-3-methyl-8-oxamoyl-6-(2-(3-thienyl)benzyl)pyrrolo [1,2-a]pyrazin-1-yl ]oxyacetate,
and the prodrugs thereof; the parent acids thereof, or their pharmaceutically acceptable salts; or their solvates.
Most preferred as sPLA2 inhibitors of the invention are
Methyl[7-ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8-oxamoylpyrrolo [1,2-a]pyrazin-1 -yl]oxyacetate,
Ethyl[7-ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1-yl]oxyacetate,
Morpholinylethyl [7-ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8-oxamoylpyrrolo[1,2-a ]pyrazin-1-yl]oxyacetate,
Sodium[7-ethyl-6-(2-(4-fluorophenyl)benzyl)-3-methyl-8-oxamoylpyrrolo[1,2-a]pyrazin-1 -y)oxyacetate,
Methyl[7-ethyl-3-methyl-8-oxamoyl-6-(2-(2-thienyl)benzyl)pyrrolo[1,2-a]pyrazin-1-yl ]oxyacetate, Ethyl [7-ethyl-3-methyl-8-oxamoyl-6-(2-(2-thienyl)benzyl)pyrrolo[1,2-a]pyrazin-1-yl ]oxyacetate,
Morpholinylethyl [7-ethyl-3-methyl-8-oxamoyl-6-(2-(2-thienyl)benzyl)pyrrolo[1,2-a]pyrazin-1-yl]oxyacetate, and
Sodium [7-ethyl-3-methyl-8-oxamoyl-6-(2-(2-thienyl)benzyl)pyrrolo[1,2-a]pyrazin- 1-yl ]oxyacetate.
The invention also relates to a pharmaceutical composition containing as active ingredient a compound as described in any one of formula (I) or (II) or (III) or (IV) supra., or as named, supra., or as tabulated in Tables 14 to 25, infra., or as described in any one of the Examples, infra.
The invention further relates to a pharmaceutical composition as described in the preceding paragraph, which is for inhibiting sPLA2.
The invention also relates to a pharmaceutical composition as described in the preceding paragraph, which is for treatment or prevention of Inflammatory Diseases.
The invention further is also a method of inhibiting sPLA2 mediated release of fatty acid which comprises contacting sPLA2 with a therapeutically effective amount of a pyrrolo[1,2-a]pyrazine compound.
The invention is also a method of treating a mammal, including a human, to alleviate the pathological effects of Inflammatory Diseases; wherein the method comprises administration to said mammal of a pyrrolo[1,2-a]pyrazine compound.
The invention further relates to a pyrrolo[1,2-a]pyrazine compound of described in any one of formula (I) or (II) or (III) or (IV) supra., or as named, supra., or as tabulated in Tables 14 to 25, infra., or as described in any one of the Examples, infra, or a pharmaceutical formulation containing an effective amount of said compound for use in treatment of Inflammatory Diseases.
The invention also relates to a compound or formulation as described in the preceding paragraph containing an effective amount of a pyrrolo[1,2-a]pyrazine compound for use as an inhibitor for inhibiting sPLA2 mediated release of fatty acid.
The invention further relates to a pyrrolo[1,2-a]pyrazine sPLA2 inhibitor substantially as hereinbefore described with reference to any of the Examples.
In the present specification, the term xe2x80x9calkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms. An example of the alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decanyl, n-undecanyl, n-dodecanyl, n-tridecanyl, n-tetradecanyl, n-pentadecanyl, n-hexadecanyl, n-heptadecanyl, n-octadecanyl, n-nonadecanyl, n-eicosanyl and the like.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one double bond. An example of the alkenyl includes vinyl, allyl, propenyl crotonyl, isopentenyl, a variety of butenyl isomers and the like.
The term xe2x80x9calkynylxe2x80x9d used in the present specification means a straight or branched chain monovalent hydrocarbon group having a specified number of carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). An example of the alkynyl includes ethynyl, propynyl, 6-heptynyl, 7-octynyl, 8-nonynyl and the like.
The term xe2x80x9ccarbocyclic groupxe2x80x9d used in the present specification means a group derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered, preferably 5 to 10 membered, and more preferably 5 to 7 membered organic nucleus whose ring forming atoms (other than hydrogen atoms) are solely carbon atoms. A group containing two to three of the carbocyclic group is also included in the above stated group. An example of typical carbocyclic groups includes (f) cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl); cycloalkenyl (such as cyclobutylenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooptenyl); phenyl, spiro[5,5]undecanyl, naphthyl, norbornyl, bicycloheptadienyl, tolyl, xylyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenylcyclohexenyl, acenaphthyl, anthoryl, biphenylyl, bibenzylyl, and a phenylalkylphenyl derivative represented by the formula: 
wherein x is an integer from 1 to 8.
The term xe2x80x9cspiro[5,5]undecanylxe2x80x9d refers to the group represented by the formula: 
Phenyl, cyclohexyl or the like is preferred as a carbocyclic groups in the R4 and R5.
The term xe2x80x9cheterocyclic groupxe2x80x9d used in the present specification means a group derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nucleus having 5 to 14 ring atoms and containing 1 to 3 hetero atoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom. An example of the heterocyclic group includes pyridyl, pyrroly], pyrrolidinyl, piperidinyl, furyl, benzofuryl, thienyl, benzothienyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl azaindolyl, benzofuranyl, benzothiophenyl, dibenzofuranyl, dibenzothiophenyl, indazolyl, imidazo[1,2-a]pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, puridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, morpholino, thiomorpholino, homopiperazinyl, tetrahydrofuranyl, tetrahydropyranyl, oxacanyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, tetrahydrothiopheneyl, pentamethylenesulfadyl, 1,3-dithianyl, 1,4-dithianyl, 1,4-thioxanyl, azetidinyl, hexamethyleneiminium, heptamethyleneiminium, piperazinyl and the like.
Furyl, thienyl or the like is preferred as a heterocyclic group in the R4 and R5.
Preferred carbocyclic and heterocyclic groups in R1 are (g) a group represented by the formula: 
wherein R13 and R14 are independently selected from a halogen, C1 to C10 alkyl, C1 to C10 alkyloxy, C1 to C10 alkylthio, aryl, heteroaryl, and C1 to C10 haloalkyl, a is an oxygen atom or a sulfur atom, L5 is xe2x80x94(CH2)vxe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94, v is an integer from 0 to 2; xcex1 is an oxygen atom or a sulfur atom; xcex2 is xe2x80x94CH2xe2x80x94or xe2x80x94(CH2)2xe2x80x94; xcex3 is an oxygen atom or a sulfur atom; b is an integer from 0 to 3, d is an integer from 0 to 4; f, p, and w are an integer from 0 to 5; r is an integer from 0 to 7, and u is an integer from 0 to 4. When the above b, d, f, p, r, u, and/or w are 2 or more, a plural number of R13 or R14 may be different from one another. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group. A more preferable example includes (h) a group represented by the formula: 
wherein R13, R14, xcex1, xcex2; and xcex3 are the same as defined above, L6 is a bond, xe2x80x94CH2xe2x80x94, xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94C xe2x89xa1Cxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94 and xcex3 is 0 or 1. When R13 is a substituent on the naphthyl group, the substituent may be substituted at any arbitrary position on the naphthyl group.
The xe2x80x9cpyrrolo[1,2-a]pyrazine nucleusxe2x80x9d is represented by the following structural formula together its numerical ring position for substituent placement: 
The term xe2x80x9cnon-interfering substituentxe2x80x9d in the present specification means a group suitable for substitution at position 3 and 4 on the pyrrolo[1,2-a]pyrazine nucleus represented by the formula (I) as well as a group suitable for substitution of the above described xe2x80x9ccarbocyclic groupxe2x80x9d and xe2x80x9cheterocyclic groupxe2x80x9d. An example of the non-interfering substituents includes C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkynyl, C7 to C12 aralkyl (such as benzyl and phenethyl), C7 to C12 alkaryl, C2 to C8 alkenyloxy, C2 to C8 alkynyloxy, C3 to C8 cycloalkyl, C3 to C8 cycloalkenyl, phenyl, tolyl, xylyl, biphenylyl, C1 to C8 alkyloxy, C2 to C12 alkyloxyalkyl (such as methyloxymethyl, ethyloxymethyl, methyloxyethyl, and ethyloxyethyl), C2 to C12 alkyloxyalkyloxy (such as methyloxymethyloxy and methyloxyethyloxy), C2 to C12 alkylcarbonyl (such as methylcarbonyl and ethylcarbonyl), C2 to C12 alkylcarbonylamino (such as methylcarbonylamino and ethylcarbonylamino), C2 to C12 alkyloxyamino (such as methyloxyamino and ethyloxyamino), C2 to C12 alkyloxyaminocarbonyl (such as methyloxyaminocarbonyl and ethyloxyaminocarbonyl), C1 to C12 alkylamino (such as methylamino, ethylamino, dimethylamino, and ethylmethylamino), C1 to C6 alkylthio, C2 to C12 alkylthiocarbonyl (such as methylthiocarbonyl and ethylthiocarbonyl), C1 to C8 alkylsulfinyl (such as methylsulfinyl and ethylsulfinyl), C1 to C8 alkylsulfonyl (such as methylsulfonyl and ethylsulfonyl), C2 to C8 haloalkyloxy (such as 2-chloroethyloxy and 2-bromoethyloxy), C1 to C8 haloalkylsulfonyl (such as chloromethylsulfonyl and bromomethylsulfonyl), C2 to C8 haloalkyl, C1 to C8 hydroxyalkyl (such as hydroxymethyl and hydroxyethyl), xe2x80x94C(O)O(C1 to C8 alkyl) (such as methyloxycarbonyl and ethyloxycarbonyl, xe2x80x94(CH2)zxe2x80x94Oxe2x80x94(C1 to C8 alkyl), benzyloxy, aryloxy (such as phenyloxy), arylthio (such as phenylthio), xe2x80x94(CONHSO2R25), xe2x80x94CHO, amino, amidino, halogen, carbamyl, carboxyl, carbalkyloxy, xe2x80x94(CH2)zxe2x80x94COOH (such as carboxymethyl, carboxyethyl, and carboxypropyl), cyano, cyanoguanidino, guanidino, hydrazido, hydrazino, hydroxy, hydroxyamino, nitro, phosphono, xe2x80x94SO3H, thioacetal thiocarbonyl, carbonyl, carbocyclic groups, heterocyclic groups and the like wherein z is an integer from 1 to 8 and R25 is C1 to C6 alkyl or aryl. These groups may be substituted by at least one substituent selected from the group consisting of C1 to C6 alkyl, C1 to C6 alkyloxy, C2 to C6 haloalkyloxy, C1 to C6 haloalkyl, and halogens.
Preferable are halogens, C1 to C6 alkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, and C1 to C6 haloalkyl as the xe2x80x9cnon-interfering substituentxe2x80x9d in the R1. More preferable are halogens, C1 to C3 alkyl, C1 to C3 alkyloxy, C1 to C3 alkylthio, and C1 to C3 haloalkyl.
Preferable are (i) C1 to C6 alkyl, aralkyl, C1 to C6 alkyloxy, C1 to C6 alkylthio, C1 to C6 hydroxyalkyl, C2 to C6 haloalkyloxy, halogens, carboxy, C1 to C6 alkyloxycarbonyl, aryloxy, arylthio, carbocyclic groups, and heterocyclic groups as the xe2x80x9cnon-interfering substituentsxe2x80x9d in the R4, R5, R10, and R11. More preferable are (0) C1 to C6 alkyl, aralkyl, carboxy, C1 to C6 hydroxyalkyl, phenyl, and C1 to C6 alkyloxycarbonyl.
The term xe2x80x9chalogenxe2x80x9d in the present specification means fluorine, chlorine, bromine, and iodine.
The term xe2x80x9ccycloalkylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms. An example of the cycloalkyl includes cydlopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
The term xe2x80x9ccycloalkenylxe2x80x9d in the present specification means a monovalent cyclic hydrocarbon group having a specified number of carbon atoms and at least one double bond(s). An example of the cycloalkenyl includes 1-cyclopropenyl, 2-cyclopropenyl, 1-cyclobutenyl, 2-cyclobutenyl and the like.
In the present specification, an example of xe2x80x9calkyloxyxe2x80x9d includes methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, n-pentyloxy, n-hexyloxy and the like.
In the present specification, an example of xe2x80x9calkylthioxe2x80x9d includes methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, n-pentylthio, n-hexylthio and the like.
The term xe2x80x9cacidic groupxe2x80x9d in the present specification means an organic group functioning as a proton donor capable of hydrogen bonding when attached to a pyrrolo[1,2-a]pyrazine nucleus through a suitable linking atom (hereinafter defined as xe2x80x9cacid linkerxe2x80x9d). An example of the acidic group includes (k) a group represented by the formula: 
wherein R18 is hydrogen atom, a metal, or C1 to C10 alkyl and each R19 is independently hydrogen atom or C1 to C10 alkyl. Preferable is (1) xe2x80x94COOH, xe2x80x94SO3H, or P(O)(OH)2. More preferable is (m)xe2x80x94COOH.
The term xe2x80x9cacid linkerxe2x80x9d in the present specification means a divalent linking group represented by a symbol xe2x80x94(L2)xe2x80x94, and it functions to join 1-position of pyrrolo[1,2-a]pyrazine nucleus to an xe2x80x9cacidic groupxe2x80x9d in the general relationship. An example of it includes (n) a group represented by the formula: 
wherein M is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R24)xe2x80x94, or xe2x80x94Sxe2x80x94, and R16 and R17 are independently hydrogen atom, C1 to C10 alkyL aryl, aralkyl, carboxy, or halogens. Preferable are (o) xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2, xe2x80x94N(R24)xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH(CH3)xe2x80x94, or xe2x80x94Oxe2x80x94CH((CH2)2Ph)xe2x80x94 wherein R24 is hydrogen atom or C1 to C6 alkyl and Ph is phenyl. More preferable is (o) xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94Sxe2x80x94CH2xe2x80x94.
In the present specification, the term xe2x80x9cacid linker lengthxe2x80x9d means the number of atoms (except for hydrogen atoms) in the shortest chain of a linking group xe2x80x94(L2)xe2x80x94which connects 1-position in pyrrolo[1,2-a]pyrazine nucleus with the xe2x80x9cacidic groupxe2x80x9d. The presence of a carbocyclic ring in xe2x80x94(L2)xe2x80x94counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene and cyclohexane ring in the acid linker counts as two atoms in culculating the length of xe2x80x94(L2)xe2x80x94. A preferable length is 2 to 3.
A symbol k in the formula (IV) is preferably 1.
The term xe2x80x9chaloalkylxe2x80x9d in the present specification means the above described xe2x80x9calkylxe2x80x9d substituted with the above described xe2x80x9chalo(genxe2x80x9d at arbitrary position(s). An example of the halo alkyl includes chloro methyl, trifluoro methyl, 2-chloroethyl, 2-bromoethyl and the like.
The term xe2x80x9chydroxyalkylxe2x80x9d in the present specification means the aforementioned xe2x80x9calkylxe2x80x9d substituted with hydroxy at arbitrary position(s). An example of the hydroxyalkyl includes hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like. In this case, hydroxymethyl is preferable.
In the present specification, the term xe2x80x9chaloalkylxe2x80x9d in xe2x80x9chaloalkyloxyxe2x80x9d is the same as defined above. An example of it includes 2-chloroethyloxy, 2,2,2-tritluoroethyloxy, 2-chloroethyloxy and the like.
The term xe2x80x9carylxe2x80x9d in the present specification means a monocyclic or condensed cyclic aromatic hydrocarbon. An example of the aryl includes phenyl, 1-naphthyl, 2-naphthyl, anthryl and the like. Particularly, phenyl, and 1-naphthyl are preferred.
The term xe2x80x9caralkylxe2x80x9d in the present specification means a group wherein the aforementioned xe2x80x9calkylxe2x80x9d is substituted with the above-mentioned xe2x80x9carylxe2x80x9d. Such aryl may have a bond at any substitutable position . An example of it includes benzyl, phenethyl, phenylpropyl (such as 3-phenylpropyl), naphthylmethyl (such as 1-naphthylmethyl) and the like.
The term, xe2x80x9cgroup containing 1 to 4 non-hydrogen atomsxe2x80x9d refers to relatively small groups which form substituents at the 7 position of the pyrrolo[1,2-a]pyrazine nucleus, said groups may contain non-hydrogen atoms alone, or non-hydrogen atoms plus hydrogen atoms as required to satisfy the unsubstituted valence of the non-hydrogen atoms, for example; (i) groups absent hydrogen which contain no more than 4 non-hydrogen atoms such as xe2x80x94CF3, xe2x80x94Cl, xe2x80x94Br, xe2x80x94NO, xe2x80x94CN, xe2x80x94SO3; and (ii) groups having hydrogen atoms which contain less than 4 non-hydrogen atoms such as xe2x80x94CH3, xe2x80x94C2H5, xe2x80x94CHxe2x95x90CH2, xe2x80x94CH(CH3)2,and cyclopropyl.
An example of the xe2x80x9calkyloxycarbonylxe2x80x9d in the present specification includes methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl and the like.
A group of preferable substituents as the R1 to R5 and the RA of the compound represented by the formula (I) will be shown in items (A) to (W). Items (f) to (m) are the same group as described above.
As the R1, (A): xe2x80x94(L1)xe2x80x94R6, (B): xe2x80x94(CH2)1-2xe2x80x94(g), (C): xe2x80x94(CH2),2xe2x80x94(g), and (D): xe2x80x94(CH,)1-2xe2x80x94(h) are preferred.
As the R2, (E): hydrogen atom, halogen, C1 to C3 alkyl, C3 to C4 cycloalkyl, or C1 to C3 alkyloxy; and (F): C1 to C3 alkyl or C3 to C4 cycloalkyl are preferred.
As the RA, (G): xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94CH2C(xe2x95x90O)xe2x80x94NH2, or xe2x80x94CH2C(xe2x95x90O) xe2x80x94NHNH2; and (H): xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94NH2 are preferred.
As the R3, (I): xe2x80x94(n)xe2x80x94(k), (J): xe2x80x94(n)xe2x80x94(I), (K): xe2x80x94(n)xe2x80x94(m), (L): xe2x80x94(o)xe2x80x94(k), (M): xe2x80x94(o)xe2x80x94(l), (N): xe2x80x94(o)xe2x80x94(m), (O): xe2x80x94(p)xe2x80x94(k), (P): xe2x80x94(p)xe2x80x94(l), and (Q): xe2x80x94(p)xe2x80x94(m) are preferred.
As the R4, (R): hydrogen atom or non-interfering substituent, (S): hydrogen atom or (i), and (T): hydrogen atom or 0) are preferred.
As the R5, (U): hydrogen atom or (i), (V): hydrogen atom or (j), and (W): hydrogen atom are preferred.
A preferred group of compounds represented by the formula (I) will be shown hereinafter.
(R1,R2,RA,R4,R5)xe2x95x90(A,E,G,R,U), (A,E,G,R,V), (A,E,G,R,W), (AE,G,S,U), (A,E,G,S,V),
(A,E,G,S,W), (A,E,G,T,U), (A,E,G,T,V), (A,E,G,T,W), (A,E,H,R,U), (A,E,H,R,V),
(A,E,H,R,W), (A,E,H,S,U), (A,E,H,S,V), (A,E,H,S,W), (A,E,H,T,U), (AE,H,T,V),
(A,E,H,T,W), (A,F,G,R,U), (AF,G,R,V), (AF,G,R,W), (A,F,G,S,U), (A,F,G,S,V),
(A,F,G,S,W), (A,F,G,T,U), (A,F,G,T,V), (AF,G,T,W), (A,F,H,R,U), (A,F,H,R,V),
(A,F,H,R,W), (A,F,H,S,U), (AF,H,S,V), (AF,H,S,W), (AF,H,T,U), (A,F,H,T,V),
(A,F,H,T,W), (B,E,G,R,U), (B,E,G,R,V), (B,E,G,R,W), (B,E,G,S,U), (B,E,G,S,V),
(B,E,G,S,W), (B,E,G,T,U), (B,E,G,T,V), (B,E,G,T,W), (B,E,H,R,U), (B,E,H,R,V),
(B,E,H,R,W), (B,E,H,S,U), (B,E,H,S,V), (B,E,H,S,W), (B,E,H,T,U), (B,E,H,T,V),
(B,E,H,T,W), (B,F,G,R,U), (B,F,G,R,V), (B,F,G,R,W), (B,F,G,S,U), (B,F,G,S,V),
(B,F,G,S,W), (B,F,G,T,U), (B,F,G,T,V), (B,F,G,T,W), (B,F,H,R,U), (B,F,H.R,V),
(B,F,H,R,W), (B,F,H,S,U), (B,F,H,S,V), (B,F,H,S,W), (B,F,H,T,U), (B,F,H,T,V).
(B ,F,H,T,W), (C,E,G,R,U), (C,E,G,R,V), (C,E,G,R,W), (C,E,G,S,U), (C,E,G,S,V),
(C,E,G,S,W), (C,E,G,T,U), (C,E,G,T,V), (C,E,G,T,W), (C,E,H,R,U), (C,E,H,R,V),
(C,E,H,R,W, (C,E,H,S,U), (C,E,H,S,V), (C,E,H,S,W), (C,E,H,T,U), (C,E,H,T,V),
(C,E,H,T,W), (C,F,G,R,U), (C,F,G,R,V), (C,F,G,R,W), (C,F,G,S,U), (C,F,G,S,V),
(C,F,G,S,W), (C,F,G,T,U), (C,F,G,T,V), (C,F,G,T,W), (C,F,H,R,U), (C,F,H,R,V),
(C,F,H,R,W), (C,F,H,S,U), (C,F,H,S,V), (C,F,H,S,W), (C,F,H,T,U), (C,F,H,T,V),
(C,F,H,T,W), (D,E,G,R,U), (D,E,G,R,V), (D,E,G,R,W), (D,E,G,S,U), (D,E,G,S,V),
(D,E,G,S,W), (D,E,G,T,U), (D,E,G,T,V), (D,E,G,T,W), (D,E,H,R,U), (D,E,H,R,V),
(D,E,H,R,W), (D,E,H,S,U), (D,E,H,S,V), (D,E,H,S,W), (D,E,H,T,U), (D,E,H,T,V),
(D,E,H,T,W), (D,F,G,R,U), (D,F,G,R,V), (D,F,G,R,W), (D,F,G,S,U), (D,F,G,S,V),
(D,F,G,S,W), (D,F,G,T,U), (D,F,G,T,V), (D,F,G,T, W), (D,F,H,R,U), (D,F,H,R,V),
(D,F,H,R,W), (D,F,H,S,U), (D,F,H,S,V), (D,F,H,S,W), (D,F,H,T,U), (D,F,H,T,V), and
(D,F,H,T,W).
Preferred embodiments of this invention are compounds wherein R3 is any one of (I) to (Q) and (R1,R2,RA,R4,R5) is any one of the above combinations.
The term, xe2x80x9cInflammatory Diseasesxe2x80x9d refers to diseases such as inflammatory bowel disease, sepsis, septic shock, adult respiratory distress syndrome, pancreatitis, trauma-induced shock, bronchial asthma, allergic rhinitis, rheumatoid arthritis, chronic rheumatism, arterial sclerosis, cereberal hemorrhage, cerebral infarction, cardiac failure, cardiac infarction, psoriasis, cystic fibrosis, stroke, acute bronchitis, chronic bronchitis, acute bronchiolitis, chronic bronchiolitis, osteoarthritis, gout, spondylarthropathris, ankylosing spondylitis, Reiter""s syndrome, psoriatic arthropathy, enterapathric spondylitis, Juvenile arthropathy or juvenile ankylosing spondylitis, Reactive arthropathy, infectious or post-infectious arthritis, gonoccocal arthritis, tuberculous arthritis, viral arthritis, fungal arthritis, syphilitic arthritis, Lyme disease, arthritis associated with xe2x80x9cvasculitic syndromesxe2x80x9d, polyarteritis nodosa, hypersensitivity vasculitis, Luegenec""s granulomatosis, polymyalgin rheumatica, joint cell arteritis, calcium crystal deposition arthropathris, pseudo out, non-articular rheumatism, bursitis, tenosynomitis, epicondylitis (tennis elbow), carpal tunnel syndrome, repetitive use injury (typing), miscellaneous forms of arthritis, neuropathic joint disease (charco and joint), hemarthrosis (hemarthrosic), Henoch-Schonlein Purpura, hypertrophic osteoarthropathy, multicentric reticulohistiocytosis, arthritis associated with certain diseases, surcoilosis, hemochromatosis, sickle cell disease and other hemoglobinopathries, hyperlipoproteineimia, hypogammaglobulinemia, hyperparathyroidism, acromegaly, familial Mediterranean fever, Behat""s Disease, systemic lupus erythrematosis, or relapsing polychondritis and related diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of the compound of formula I in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products.
The terms, xe2x80x9cmammalxe2x80x9d and xe2x80x9cmammalianxe2x80x9d include human.
The term xe2x80x9csolvatexe2x80x9d includes, for example, solvates with organic solvents, hydrates, and the like.
The compounds of the invention represented by the general formula (I) can be synthesized in accordance with the following methods A to I. 
wherein R2, R4, R5, R6 , R22, X, Y, and L4 are as defined above; R26 R27, and R28 are C1 to C3 alkyl; Hal is a halogen, and Met is an alkali metal.
(Step 1)
The present step is the one for constructing pyrrolo[1,2-a]pyrazine ring, and it may be conducted in accordance with a process described in J. Chem. Soc., Perkin Trans. 1, 1990, 311-314 (The disclosure of which are incorporated herein by reference).
(Step 2)
The present step is the one for transforming the ketone at 1-position into an alkyloxy group. To the compound (VII) is added a halogenating agent such as phosphorus oxychloride, phenylphosphonic dichloride and the like, and the resulting mixture is refluxed for 1 to 8 hours, preferably 3 to 5 hours. The resulting compound is dissolved in an alcohol (for example, methanol, ethanol, and n-propanol), an alkali metal compound of C1 to C3 alcohol (for example, sodium methoxide, and sodium ethoxide), sodium p-toluenesulfinate and the like are added to the solution, and the mixture is stirred at 70xc2x0 C. to 120xc2x0 C., preferably 80xc2x0 C. to 100xc2x0 C. for 5 to 36 hours, preferably 12 to 24 hours. When the resulting product is subjected to a usual work-up, the compound (VIII) can be obtained.
(Step 3)
The present step is the one for introducing a substituent to 6-position of pyrrolo[1,2-a]pyrazine, and it may be carried out by Friedelxe2x80x94Crafts reaction. The compound (VIII) is dissolved in a solvent such as 1,2-dichloroethane, methylene chloride and the like, R6COHal and Lewis acid (for example, AlCl3, SbF5, BF3 and the like) are added gradually to the solution at xe2x88x9278xc2x0 C. to 10xc2x0 C., preferably xe2x88x9220xc2x0 C. to ice-cooling, and the resulting mixture is stirred at xe2x88x9210xc2x0 C. to 10xc2x0 C., preferably 0xc2x0 C. to 10xc2x0 C. for 5 to 30 minutes, preferably 10 to 20 minutes. Alternatively, the reaction may be carried out in such that the compound (VIII) is dissolved in R6COHal without using any solvents, and then, the step is continued in accordance with the same manner as that described above. When the resulting product is subjected to a usual work-up, the compound (IX) can be obtained (see J. Med. Chem., 39, 3636-58 (1996). The disclosure of which are incorporated herein by reference.)
(Step 4)
The present step is the one for reducing the carbonyl group at 6-position of pyrrolo[1,2-a]pyrazine to transform the same into methylene. Lewis acid (for example, AlCl3 and the like) is dissolved in a solvent such as methylene chloride, tetrahydrofuran and the like, a reducing agent such as boron-t-butylamine complex, sodium borohydride and the like is added to the solution at xe2x88x9220xc2x0 C. to 10xc2x0 C., preferably under ice-cooling, and the resulting mixture is stirred for 5 to 30 minutes, preferably 10 to 20 minutes. The compound (IX) dissolved in methylene chloride, tetrahydrofuran and the like is added to the reaction mixture at xe2x88x9220xc2x0 C. to 10xc2x0 C., preferably under ice-cooling, the resulting mixture is stirred preferably for 20 to 30 minutes, and further the stir is continued at 15xc2x0 C. to 40xc2x0 C., preferably 20xc2x0 C. to 30xc2x0 C. for 1 to 5 hours, preferably 2 to 3 hours. When the resulting product is subjected to a usual work-up, the compound (X) can be obtained (see J. Med. Chem., 39, 3635-58 (1996). It is to be noted that The disclosure of which are incorporated herein by reference.)
(Step 5)
The present step is the one for transforming the alkyloxy group into ketone. An acid such as concentrated hydrochloric acid and the like is added to the compound (X), and the mixture is stirred at 80xc2x0 C. to 150xc2x0 C., preferably 100xc2x0 C. to 120xc2x0 C. for 1 to 5 hours preferably 2 to 3 hours. When the resulting product is subjected to a usual work-up, the compound (XI) can be obtained.
(Step 6)
The present step is the one for transforming the ketone at 1-position into a halogen. A halogenating agent such as phosphorus oxychloride, phenylphosphonic dichloride and the like is added to the compound (XI), and the mixture is refluxed for 1 to 8 hours, preferably 3 to 5 hours. When the resulting product is subjected to an ordinary work-up, the compound (XII) can be obtained.
(Step 7)
The present step is the one for transforming the halogen at 1-position into (xe2x80x94L4xe2x80x94R22). To a suspension of R22xe2x80x94L4xe2x80x94H and an alkali metal compound such as sodium and the like are added the compound (XII) and sodium p-toluenesulfinate or the like, and the mixture is stirred at 70xc2x0 C. to 120xc2x0 C., preferably 80xc2x0 C. to 100xc2x0 C. for 5 to 36 hours, preferably 12 to 24 hours. When the resulting product is subjected to an ordinary work-up, the compound (XIII) can be obtained.
(Step 8)
The present step is the one for introducing a substituent to 8-position. The compound (XIII) is dissolved in a solvent such as 1,2-dichloroethane, tetrahydrofuran and the like, Halxe2x80x94C(xe2x95x90X)xe2x80x94C(xe2x95x90X)xe2x80x94Hal (for example, oxalyl chloride) and a base such as N-methylmorpholine, triethylamine and the like are added to the solution, and the mixture is stirred at 30xc2x0 C. to 70xc2x0 C., preferably 40xc2x0 C. to 60xc2x0 C. for 1 to 10 hours, preferably 3 to 6 hours. The reaction mixture is poured into cold aqueous ammonia, and the resulting mixture is stirred for 5 to 30 minutes, preferably 10 to 20 minutes. When the resulting product is subjected to an ordinary work-up, the compound (XV) can be obtained. 
wherein R2, R4, R6, R22, R28, L4, X, Y, and Hal are as defined above, and R5 is hydrogen.
(Step 1)
The present step is the one for constructing pyrazine ring, and it may be carried out in accordance with the process described in J. Am. Chem. Soc., 74, 1580-84 (1952). (The disclosure of which are incorporated herein by reference.)
(Step 2)
The present step may be carried out in accordance with the same manner as that of the method Axe2x80x94step 2.
(Step 3)
The present step is the one for constructing pyrrolo[1,2-a]pyrazine ring. A mixture of the compound (XIX) and Halxe2x80x94CH2xe2x80x94C(xe2x95x90O)xe2x80x94R2 is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50xc2x0 C to 70xc2x0 C. for 3 to 36 hours, preferably 12 to 24 hours to obtain a quaternary salt. The resulting quaternary salt is dissolved in a solvent such as 1,2-dichloroethane, acetonitrile and the like, a base such as 1,8-diazabicyclo[5,4,0]-undec-7-ene(DBU), triethylamine and the like is added to the solution, and the mixture is stirred at 40xc2x0 C. to 90xc2x0 C., preferably 50xc2x0 C. to 70xc2x0 C. for 3 to 36 hours, preferably 12 to 24 hours. When the resulting product is subjected to a usual work-up, the compound (XXI) can be obtained.
(Step 4)
The present step may be carried out in accordance with the same manner as that of the method Axe2x80x94step 3.
(Step 5)
The present step may be carried out in accordance with the same manner as that of the method Axe2x80x94steps 4 to 8. 
wherein R4, R5, and Hal are as defined above, and Boc is t-butoxycarbonyl.
(Step 1)
The present step is the one for conducting condensation reaction of the compound (XXIII) and the compound (XXIV). The compound (XXIII) is dissolved in a solvent such as tetrahydrofuran, dichloromethane, acetonitrile and the like, the compound (XXIV) and a condensation agent such as N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3xe2x80x94(3-dimethylaminopropyl)carbodiimide (WSCD), N,N-dicarbonylimidazole, 2-halo-1-methylpyridinium iodide, di-2-pyridyl carbonate, 1,1xe2x80x2-oxalyldiimidazole and the like are added to the solution, and the resulting mixture is reacted at xe2x88x9220xc2x0 C. to 80xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 1 to 30 hours, preferably 3 to 20 hours to obtain the compound (XXV).
(Step 2)
The present step is the one for effecting oxidation of hydroxyl group and ring closure reaction.
The oxidation reaction may be carried out in accordance with a manner applied generally. In this respect, the following four types of oxidation reaction are particularly preferred.
i) PCC Oxidation (The compound (XXV) is dissolved in a solvent such as dichloromethane and the like, pyridinium chlorochromate (PCC) is added to the solution, and the mixture is allowed to react at xe2x88x9220xc2x0 C. to 60xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 1 to 30 hours, preferably 3 to 20 hours, to give an oxidized product.) (see Tetrahedron Lett., 2647-2650 (1975))
ii) Swern Oxidation (Dichioromethane is cooled to xe2x88x9278xc2x0 C., oxalyl chloride, dimethyl sulfoxide, and the compound (XXV) are added successively to the solvent. The mixture is allowed to warm to xe2x88x9245xc2x0 C. to 0xc2x0 C., the mixture is allowed to react for 1 to 30 hours, preferably 1 to 10 hours. When the resulting product is subjected to a usual work-up, a aimed compound can be prepared.) (see J. Org. Chem., 43, 2480-2482 (1978))
iii) Dess-Martin Oxidation (A solution of Dess-Martin reagent in dimethyl sulfoxide or the like is allowed to react with compound (XXV) in a solvent such as tetrahydrofuran.) (see J. Org. Chem., 48, 4155-4156 (1983))
iv) Oxidation by Halogen Oxoacid (The compound (XXV) is allowed to react with an oxidizing agent such as halogen oxoacid and the like in the presence of 2,2,6,6-tetramethyl-1-piperizinyloxy (TEMPO) according to the process described in a literary document (J. Org. Chem., 52, 2559-2562 (1987)), whereby the compound can be prepared. In stead of TEMPO, 4-acetylamino-2,2,6,6-tetramethyl-l-piperidinyloxy, 4-benzoyloxy-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-cyano-2,2,6,6-tetramethyl-1-piperidinyloxy or the like may be used. As the halogen oxoacid, sodium hypochlorite, sodium hypobromite, sodium bromite or the like is used. As the solvent, ethyl acetate, acetonitrile, dichloromethane or the like may be used.)
In ring closure reaction, the oxidized product prepared in accordance with the above step is dissolved in a solvent such as toluene, ethyl acetate, chloroform and the like, and the solution is allowed to react at xe2x88x9210xc2x0 C. to 80xc2x0 C., preferably 0xc2x0 C. to 40xc2x0 C. for 1 to 30 hours, preferably 5 to 20 hours, whereby the compound (XXVI) can be obtained. In the case where progress of the reaction is slow, it is sufficient to add a catalytic amount of a suitable acid (for example, p-toluenesulfonic acid and the like) to the solution.
(Step 3)
The present step is the one for deprotecting Boc group. The compound (XXVI) is dissolved in a solvent such as dichloromethane, ethyl acetate, toluene and the like, a mineral acid (for example, HCl, HBr, HI and the like) or an organic acid (for example, trifluoroacetic acid, camphorsulfonic acid and the like) is added to the solution, and the mixture is allowed to react at 0xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C. for 1 to 20 hours, preferably 3 to 10 hours, whereby the compound (XXVII) can be prepared.
(Step 4)
The present step is the one for conducting dehydrogenation reaction. The compound (XXVII) is dissolved in a solvent such as decaline, quinoline, naphthalene and the like, Pd, Pt, Rh, Ni, S, or Se is added to the solution, and the mixture is allowed to react at 100xc2x0 C. to 350xc2x0 C. for 2 to 5 hours, whereby the compound (XVIII) can be obtained. In the case when a hydrogen receptor such as cyclohexene, maleic acid, and the like is allowed to exist in the reaction system, it is sufficient to be a reaction temperature of 100xc2x0 C. to 150xc2x0 C. 
wherein R4 and R5 are as defined above.
(Step 1)
The present step may be carried out in accordance with the same manner as that of the method Cxe2x80x94step 1.
(Step 2)
The present step may be carried out in accordance with the same manner as that of the oxidation step in the method Cxe2x80x94step 2.
(Step 3)
The present step is the one for oxidizing methylene to form ketone. The compound (XXX) is dissolved in dichloromethane-methanol, ethyl acetate or the like, and ozone gas is bubbled through the solution at xe2x88x9278xc2x0 C. to 0xc2x0 C., preferably xe2x88x9278xc2x0 C. to xe2x88x9230xc2x0 C. After 5 minutes to 1 hour, dimethyl sulfide or triphenylphosphine is added to the resulting mixture, and the mixture is allowed to react at 0xc2x0 C. to 60xc2x0 C., preferably 10xc2x0 C. to 40xc2x0 C. for 1 to 2 hours, whereby the compound (XXXI) can be obtained.
(Step 4)
The present step is the one for effecting ring closure reaction. The compound (XXXI) is dissolved in a solvent such as ethanol and the like, ammonium acetate is added to the solution, and the mixture is refluxed for 5 minutes to 1 hour, whereby the compound (XVIII) can be prepared. 
wherein R2, R4, R5, R22, L4, X and Y are as defined above, R29 is aryl or heteroaryl having a leaving group such as halogen, triilate, R30 is aryl or heteroaryl substituted with aryl, heteroaryl, substituted vinyl, substituted acetylene, alkyl, aryloxy and the like.
(Step 1)
The present step is a step of a carbon-carbon bond forming reaction by Suzuki reaction or Sonogashira reaction using a palladium catalyst. By the present reaction, the compound (XXXII) is converted into the compound (XXXIII) in accordance with the methods described in Syn. Commun., 11, 513 (1981) (The disclosure of which are incorporated herein by reference), Tetrahedron Lett., 4467 (1975) (The disclosure of which are incorporated herein by reference) and the like.
Compound (XXXII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having a B(OH)2 (otherwise B(Et)2) group such as phenylboronic acid in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(Ph3,P)4) and a base (e.g., potassium carbonate, calcium carbonate, triethylamine, sodium methoxide etc.) to give the desired compound (XXXIII). This reaction is carried out at 0 to 100xc2x0 C., preferably 0 to 80xc2x0 C. This reaction is completed for 5 to 50 hours, preferably 15 to 30 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of xe2x80x9cProtective Groups in Organic Synthesis xe2x80x9d ( Theodora W. Green (John Wiley and Sons)) and then deprotected at an appropriate step.
Compound (XXXII) is reacted with optionally substituted aryl or optionally substituted heteroaryl having an ethynyl group such as ethynylbenzene in a solvent such as dimethylformamide, toluene, xylene, benzene, tetrahydrofuran etc. in the presence of a palladium catalyst (e.g., Pd(Ph3P)2Cl2), a divalent copper reagent (e.g., CuI), and an organic base (e.g., triethylamine, and diisopropylethylamine) to give a desired compound (XXXIII). This reaction is carried out at 0 to 100xc2x0 C., preferably 20 to 80xc2x0 C. This reaction is completed for 3 to 30 hours, preferably 10 to 20 hours. When optionally substituted aryl or optionally substituted heteroaryl has a substituent(s) interfering this reaction, the substituent(s) can previously be protected in accordance with a method of xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d ( Theodora W. Green (John Wiley and Sons)), and then deprotected at an appropriate step.
In case that R30 is aryl or heteroaryl substituted with aryloxy, the compound (XXXII) is dissolved in a solvent such as pyridine, and then cooper (II) oxide, a base (for example, potassium carbonate) and substituted phenols are added, and the resulting mixture was stirred at 10 to 150xc2x0 C., preferably 100 to 150xc2x0 C., for 1 to 24 hours, preferably 5 to 10 hours. The compound (XXXIII) is obtained by the usual work-up.
(Step 2)
The present step can be carried out in the same manner as those described in step 6 to 8 of Method A 
wherein R2, R4, R5, R6, R22, X and Y are as defined above.
When L4 is CH2S in Method A, (XXXVII) can also be synthesized by Method F.
(Step 1)
The present step is a step wherein the ketone group at C1-position is converted into thioketone. The reaction may be conducted in accordance with the method described in Monatsh chem, 126, 747 (1995) (The disclosure of which are incorporated herein by reference). The compound (XI) is dissolved in a solvent such as pyridine, and the resulting mixture is stirred with phosphorus pentasulfide at 10xc2x0 C. to 150xc2x0 C., preferably 100 to 150xc2x0 C., for 1 to 5 hours, preferably 2 to 3 hours. The compound (XXXV) is obtained by the usual work-up. This step can also be conducted by reacting with compound (XI) and Lawesson reagent in a solvent such as tetrahydrofuran, dimethylformamide at 10 to 150xc2x0 C., preferably 50 to 100xc2x0 C., for 1 to 5 hours, preferably 2 to 3 hours.
(Step 2)
The present step is a step wherein the thioketone group at C1-position is converted into iminosulfide group.
The compound (XXXV) is dissolved in a solvent such as tetrahydrofuran, dimethylformamide, R22CH2X (for example, bromoacetic acid methyl ester) and a base (for example, potassium carbonate) are added, and the resulting mixture is stirred at 0 to 100xc2x0 C., preferably 10 to 50xc2x0 C., for 1 to 5 hours, preferably 1 to 2 hours. The compound (XXXVI) is obtained by the usual work-up.
(Step 3)
The present step can be carried out in the same manner as that described in step 8 of Method A. 
wherein R2, R4, R6, R22, R28, L4, Hal, X and Y are as defined above, R31L is C1-C3 alkyl or aryl.
(Step 1)
The present step is a step wherein a substituent is introduced to C4-position of pyrrolo[1,2-a]pyrazine without any substituent at C4-position. The compound (XXXVIII) is dissolved in a solvent such as diethyl ether, tetrahydrofuran, an alkyllithium (for example, methyllithium, n-butyllithium) was added at xe2x88x9278 to 10xc2x0 C., preferably xe2x88x9230xc2x0 C. to ice-cooling, and then the resulting mixture is stirred for 15 minutes to 1 hour, preferably 15 to 30 minutes. R6xe2x80x94CHO is added to the above mixture and the mixture was stirred further 15 minutes to 1 hour, preferably 15 to 30 minutes. The compound (XXXIX) is obtained by the usual work-up.
(Step 2)
The present step is a step wherein the hydroxyl group at C4-position of pyrrolo[1,2-a]pyrazine is reduced, and converted into methylene group. The reaction can be conducted in accordance with the method described in Tetrahedron, 51, 11043 (1995) (The disclosure of which are incorporated herein by reference). Alternatively, the reaction may be conducted in accordance with the above step 4 of Method A, a catalytic hydrogenation method by using a reduction catalyst such as palladium-carbon and source of hydrogen such as hydrogen gas, ammonium formate (refer to Synth. Commun., 22, 2673 (1992), The disclosure of which are incorporated herein by reference), a method by using samarium iodide (refer to Tetrahedron Lett., 30, 2945 (1989), The disclosure of which are incorporated herein by reference) and the like.
(Step 3)
The present step can be carried out in the same manner as that described in step 5 of Method A
(Step 4)
The present step can be carried out in the same manner as that described in step 6 of Method A.
(Step 5)
The present step is a step wherein chloro group at C1-position of pyrrolo[1,2-a]pyrazine is converted to sulfonyl group. The compound (XLII) is dissolved in an alcoholic solvent such as ethanol or dimethyl sulfoxide, a sulfinate salt (for example, sodium p-toluenesulfinate) was added, and then the resulting mixture is stirred at 10 to 150xc2x0 C., preferably 50 to 100xc2x0 C., for 1 to 18 hours, preferably 3 to 8 hours. The catalytic amount of acid (for example, hydrochloric acid) may be added preferably. The compound (XLIII) is obtained by the usual work-up.
(Step 6)
The present step can be carried out in the same manner as that described in step 7 of Method A.
(Step 7)
The present step can be carried out in the same manner as that described in step 8 of Method A 
wherein R1, R2, R22 , L4, X, Y and Hal are as defined above, R32 and R35 are C1-C3 alkyl, R33 is lower alkyl, or a group which forms 1,3-dioxolane ring or 1,3-dioxane ring together with the adjacent oxygen atoms, R34 is hydrogen atom, C1-C6 alkyl, C7-C12 aralkyl, C1-C6 alkyloxy, C1-C6 alkylthio, C1-C6 hydroxyalkyl, C2-C6 haloalkyloxy, halogen, carboxy, C1-C6 alkyloxycarbonyl, aryloxy, arylthio, a carbocyclic group or a heterocyclic group, Met is metal.
(Step 1)
The compound (XLVI) is dissolved in a solvent such as dimethylfomamide, an aikyl halide derivative (for example, bromoacetaldehyde ethyleneacetal and the like) and a base (for example, potassium carbonate, potassium t-butoxide, sodium hydride and the like) are added , and then the resulting mixture is stirred at 10 to 80xc2x0 C., preferably 20 to 60xc2x0 C., for 3 to 80 hours, preferably 5 to 70 hours. The compound (XLVII) is obtained by the usual work-up.
(Step 2)
The present step is a step of decarboxylation reaction. The compound (XLVII) is dissolved in a solvent such as dimethyl sulfoxide, a reagent such as potassium acetate, sodium acetate are added, and then the resulting mixture is stirred at 20 to 200xc2x0 C., preferably 100 to 180xc2x0 C., for 1 to 20 hours, preferably 3 to 15 hours. The compound (XLVIII) is obtained by the usual work-up.
(Step 3)
The present step is a step of addition reaction of alkyl metal reagent to nitrile group. A solution of the compound (XLVIII) in diethyl ether, tetrahydrofuran, dimethoxyethane or the like is added to Grignard reagent (R1MgHal, Hal is halogen) or a solution of R1Li in diethyl ether, tetrahydrofuran or dimethoxyethane at xe2x88x9220 to 30xc2x0 C., and the mixture is stirred at 0 to 70xc2x0 C, preferably 20 to 60xc2x0 C, for 1 to 20 hours, preferably 2 to 10 hours. The compound (IL) is obtained by the usual work-up by using an acid such as diluted sulfuric acid.
(Step 4)
The present step is a step for constructing pyrrole ring. The compound (IL) is dissolved in a solvent such as tetrahydrofuran, substituted allylamine and a catalytic amount of an acid (for example, 1N hydrochloric acid) are added, and then the mixture is stirred at 0 to 100xc2x0 C, preferably 0 to 50xc2x0 C, for 1 to 5 hours, preferably 1 to 2 . The compound (L) is obtained by the usual work-up. Alternatively, the compound (IL) is converted into ketoaldehyde derivative by hydrolysis of acetal portion using an acid such as hydrochloric acid in a solvent such as tetrahydrofuran. Subsequently, the mixture is treated with substituted abylamine in a suitable solvent at 0 to 100xc2x0 C., preferably 0 to 50xc2x0 C., for 1 to 5 hours, preferably 1 to 2 hours to obtain the compound (L).
(Step 5)
The present step is a step for introducing alkoxycarbonyl group to pyrrole ring. The reaction can be carried out as described in step 3 of Method A by using chlorocarbonate. Alternatively, the compound (L) is converted into trichloroacetyl form by stirring it with trichloroacetyl chloride in a solvent such as tetrahydrofuran at 0 to 100xc2x0 C., preferably 10 to 40xc2x0 C., for 1 to 5 hours, preferably 1 to 2 hours. Subsequently, in a suitable alcohol, the mixture is treated with metal alkoxide of the same alcohol at 0 to 100xc2x0 C., preferably 10 to 60xc2x0 C., for 1 to 5 hours, preferably 1 to 2 hours to obtain the compound (LI).
(Step 6)
The present step is a step for constructing pyrrolomorpholine ring by iodo lactonization reaction. The compound (LI) is dissolved in a solvent such as acetonitrile, iodine was added, and the mixture is stirred at 0 to 50xc2x0 C., preferably 10 to 30xc2x0 C., for 1 to 10 hours, preferably 1 to 3 hours. The compound (LII) is obtained by the usual work-up.
(Step 7)
The present step is a step for forming double bond by eliminating HI. The compound (LII) is dissolved in a solvent such as toluene, acetonitrile, tetrahydrofuran, a base such as 1,8-diazabicyclo[5.4.0]-7-undecene is added, and the mixture is stirred at 0 to 100xc2x0 C., preferably 20 to 80xc2x0 C., for 1 to 5 hours, preferably 1 to 3 hours. The compound (LIII) is obtained by the usual work-up.
(Step 8)
The present step is a step for constructing pyrrolo[1,2-a]pyrazine ring, and can be conducted in accordance with the method described in J. Org. Chem., 53, 4650 (1988) (The disclosure of which are incorporated herein by reference). The compound (LIII) is dissolved in an alcoholic solvent or a solvent such as acetonitrile, tetrahydrofuran, a source of ammonia such as ammonium acetate is added, and the mixture is stirred at 0 to 100xc2x0 C., preferably 20 to 80xc2x0 C., for 3 to 24 hours, preferably 5 to 18 hours. The compound (LIV) is obtained by the usual work-up.
(Step 9)
The present step can be carried out in the same manner as those described in steps 6 to 8 of Method A. 
wherein R2, R6, R22, R26, R34, L4, X, Y and Hal are as defined above.
(Step 1)
The present step can be carried out in the same manner as that described in step 3 of Method A
(Step 2)
The present step can be carried out in the same manner as that described in step 4 of Method A
(Step 3)
The present step is a step of allylation of nitrogen at N1-position of pyrrole. The compound (LVII) is dissolved in a solvent such as tetrahydrofuran, dimethylformamide, allyl halide derivative and a base (for example, sodium hydride, potassium carbonate) is added, and the mixture is stirred at 0 to 100xc2x0 C., preferably 0 to 50xc2x0 C., for 1 to 10 hours, preferably 1 to 3 hours. The compound (LVIII) is obtained by the usual work-up.
(Step 4)
The present step can be carried out in the same manner as those described in steps 6 to 9 of Method H.
Where a compound of the present invention has an acidic or basic functional group, a variety of salts each having higher water solubility and more physiologically suitable properties than those of the original compound can be formed. An example of typical pharmaceutically acceptable salts includes salts with alkali metal and alkaline earth metal such as lithium, sodium, potassium, magnesium, aluminum and the like, but it is to be noted that such pharmaceutically acceptable salts are not limited thereto. A salt is easily manufactured from a free acid by either treating an acid in a solution with a base, or allowing an acid to be in contact with an ion exchange resin. Addition salts of the compounds according to the present invention with relatively non-toxic inorganic bases and organic bases, for example, amine cation, ammonium, and quaternary ammonium derived from nitrogenous bases having a basicity sufficient for forming a salt of the compounds of the present invention are included in the definition of xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d. (e.g., S. M. Berge et al., xe2x80x9cPharmaceutical Salts,xe2x80x9d J. Phar. Sci., 66, 1-19 (1977)) Furthermore, basic groups of a compound according to the present invention are reacted with a suitable organic or inorganic acid to form salts such as acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartarate, borates, bromides, camcyrates (phonetic), carbonates, chlorides, clubranates (phonetic), citrates, edetates (phonetic), edicirates (phonetic), estrates (phonetic), ethylates, fluorides, fumarates, gluseptates (phonetic), gluconates, glutamates, glycolialsanyrates (phonetic), hexylresorcinates, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, malseates (phonetic), manderates (phonetic), methylates, methylbromides, methylnitrates, methylsulfates, mucates, napcylates (phonetic), nitrates, oleates, oxarates, palnitates, pantothenates, phosphates, polygalacturonates, salicirates, stearates, subacetates (phonetic), sucinates (phonetic), tanates (phonetic), tartrates, tosylates, trifluoroacetates, trifluoromethanesulfonates, valerates and the like. In case of forming a hydrate, a questioned compound may be coordinated with a suitable number of water molecules.
In the case where a compound of the present invention has one or more of chiral center(s), it may exist as an optically active member. Likewise, in the case where a compound contains alkenyl or alkenylene, there is a possibility of cis- and trans-isomers. Mixtures of R- and S-isomers as well as of cis- and trans-isomers, and mixtures of R- and S-isomers containing racemic mixture are included in the scope of the present invention. Asymmetric carbon atom may exist also in a substituent such as alkyl group. All such isomers are included in the present invention together with these mixtures. In the case where a specified streoisomer is desired, either it is manufactured by applying a manner which has been well known by those skilled in the art wherein a starting material having an asymmetrical center which has been previously separated is subjected to stereospecific reaction to the starting material, or it is manufactured by preparing a mixture of stereoisomers, and thereafter separating the mixture in accordance with a well-known manner. For example, a racemic mixture may be reacted with a single enantiomer of some other compound. This changes the racemic form into a mixture of diastereomers and diastereomers, because they have different melting points, different boiling points, and different solubilities can be separated by conventional means, such as crystallization.
Prodrug is a derivative of the compound having a group which can be decomposed chemically or metabolically, and such prodrug is a compound according to the present invention which becomes pharmaceutically active by means of solvolysis or by placing the compound in vivo under a physiological condition. Although a derivative of the compounds according to the present invention exhibits activity in both forms of acid derivative and basic derivative, acid derivative is more advantageous in solubility, tissue affinity, and release control in mammal organism (Bungard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam, 1985). Ester prodrugs are well known (see, Silverman, Richard B, The Organic Chemistry of Drug Design and Drug Action, Chapter 8, New York, N.Y. Academic Press, ISBN 0-12-643730-0) and are a preferred prodrug form for the compounds of this invention and also for prodrugs used in the method of treating Inflammatory Disease as taught herein. For instance, prodrugs each containing an acid derivative such as an ester which is prepared by reacting a basal acid compound with a suitable alcohol, or an amide which is prepared by reacting a basal acid compound with a suitable amine are well known by those skilled in the art. Simple aliphatic or aromatic esters derived from acid groups contained in the compounds according to the present invention are preferable prodrugs. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl n-butyl, isobutyl, tert-butyl morpholinoethyl, and N,N-diethylglycolamido.
Methyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with iodo methane (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 28,956-6).
Ethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with iodo ethane (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 1-778-0).
N,N-diethylglycolamido ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 2-chloro-N,N-diethylacetamide (available from Aldrich Chemical Co., Milwaukee, Wis. USA; Item No. 25,099-6).
Morpholinylethyl ester prodrugs may be prepared by reaction of the sodium salt of a compound of Formula (I) (in a medium such as dimethylformamide) with 4xe2x80x94(2-chloroethyl)morpholine hydrochloride (available from Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).
Double ester such as (acyloxy)alkyl ester or ((alkyloxycarbonyl)oxy)alkyl ester type prodrugs may be optionally manufactured.
The term xe2x80x9cinhibitxe2x80x9d means that release of fatty acid started by sPLA2 decreases significantly by the compounds of the present invention from viewpoint of prevention and treatment of disease. The term xe2x80x9cpharmaceutically acceptablexe2x80x9d means that carriers, diluents, or additives are compatible with other ingredients in a formulation and are not harmful for recipients.
The compounds of the present invention exhibit sPLA2 inhibiting activity as per the description of the experimental examples which will be described hereinafter. Accordingly, when a curatively effective amount of the compounds represented by the formulae (I), (II), (III), and (IV), the prodrug derivatives thereof, or their pharmaceutically acceptable salts, or their solvates is administered to any of mammals (including human being), it functions effectively as a curative medicine for diseases of septic shock, adult respiratory distress syndrome, pancreatitis, injury, bronchial asthma, allergic rhinitis, chronic rheumatism, arterial sclerosis, cerebral hemorrhage, cerebral infarction, inflammatory colitis, mange, cardiac failure, cardiac infarction.
The compounds of the present invention may be administered to a patient through a variety of routes including oral, aerosol, rectal, percutaneous, subcutaneous, intravenous, intramuscular, and nasal routes. A formulation according to the present invention may be manufactured by combining (for example, admixing) a curatively effective amount of a compound of the present invention with a pharmaceutically acceptable carrier or diluent. The formulation of the present invention may be manufactured with the use of well-known and easily available ingredients in accordance with a known method.
In case of manufacturing a composition according to the present invention, either active ingredients are admixed with a carrier, or they are diluted with a carrier, or they are contained in a carrier in the form of capsule, sacheier (phonetic), paper, or another container. In case of functioning a carrier as a diluent, the carrier is a solid, semi-solid, or liquid material which functions as a medium. Accordingly, a formulation according to the present invention may be produced in the form of tablet, pill, powder medicine, intraoral medicine, elixir agent, suspending agent, emulsifier, dissolving agent, syrup agent, aerosol agent (solid in liquid medium), and ointment. Such a formulation may contain up to 10% of an active compound. It is preferred to prepare a compound according to the present invention prior to administration.
Any suitable carrier which has been well known by those skilled in the art may be used for the formulation. In such formulation, a carrier is in the form of solid, liquid, or a mixture of solid and liquid. For instance, a compound of the present invention is dissolved into 4% dextrose/0.5% sodium citrate aqueous solution so as to be 2 mg/ml concentration for intravenous injection. Solid formulation includes powder, tablet, and capsule. Solid carrier consists of one or more of material(s) for serving also as fragrant, lubricant, dissolving agent, suspension, binder, tablet disintegrator, capsule. A tablet for oral administration contains a suitable excipient such as calcium carbonate, sodium carbonate, lactose, calcium phosphate and the like together with a disintegrator such as corn starch, alginic acid and the like and/or a binder such as gelatin, acacia and the like, and a lubricant such as magnesium stearate, stearic acid, talc and the like.
In a powder medicine, a carrier is a finely pulverized solid which is blended with finely pulverized active ingredients. In a tablet, active ingredients are admixed with a carrier having required binding power in a suitable ratio, and it is solidified in a desired shape and size. Powder medicine and tablet contain about 1 to about 99% by weight of the active ingredients being novel compounds according to the present invention. An example of suitable solid carriers includes magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methyl cellulose, sodium carboxymethylcellulose, low-melting wax, and cocoa butter.
An axenic liquid formulation contains suspending agent, emulsifier, syrup agent, and elixir agent. Active ingredients may be dissolved or suspended into a pharmaceutically acceptable carrier such as sterile water, a sterile organic solvent, a mixture thereof and the like. Active ingredients may be dissolved frequently into a suitable organic solvent such as propylene glycol aqueous solution. When finely pulverized active ingredients are dispersed into aqueous starch, sodium carboxylmethylcellulose solution, or suitable oil, the other compositions can be prepared.
A lyophilized preparation may be prepared by dissolving active ingredients in a solution such as water, if necessary, with a solubilizer such as citric acid, edetic acid, polyphosphoric acid and their salts and a stabilizer such as mannitol, xylitol, sorbitol, glucose, fructose, lactose and maltose and lyophilizing it.
While a dosage differs dependent upon a state of disease, a route of administration, patient""s age, and a body weight, it is usually 0.01 to 50 mg/kg/day in case of oral administration in adult.
The method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting mammalian sPLA2 with a therapeutically effective amount of a pyrrolo[1,2-a]pyrazine sPLA2 inhibitors (and formulation containing such inhibitors) as taught, supra.
Preferably compounds of the invention (per Formula (I) or (II) or (III) or (IV) or pharmaceutical formulations containing these compounds) are in unit dosage form for administration to a mammal. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of Active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration.
The improved method of treatment for sepsis using the pyrrolo[1,2-a]pyrazine sPLA2 inhibitors (and formulation containing such inhibitors) may be practiced as follows:
The inhibitors of this invention are given by injection, either subcutaneously or into muscle tissue or by injection into a vein. Intravenous injection is the preferred mode of delivery to the mammal being treated and offers the advantage of a quick effect and rapid access into the circulation system, particularly in emergency situations.
It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic Compound (I) dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an Active ingredient of this invention.
This invention is a method of treating or preventing Inflammatory diseased, (e.g., sepsis, rheumatoid arthritis, osteoarthritis, asthma) by administering to a mammal in need thereof a therapeutically effective amount inhibitor. The administration to a septic patient may be either continuous or intermittent.
The decision to begin the therapy for sepsis will be based upon the appearance of the clinical manifestations of sepsis or laboratory tests which show initiation of the sepsis cascade (inclusive of renal complications or coagulation abnormalities or multiple organ failure). Typical clinical manifestations are fever, chills, tachycardia, tachypnea, altered mental state, hypothermia, hyperthermia, accelerated or repressed breathing or heart rates, increased or decreased white blood cell count, and hypotension. These and other symptoms are well known in the art as set out in standard references such as, Harrison""s Principles of Internal Medicine (ISBN 0-07-032370-4) 1994, pages 511-515.
The decision to determine the length of therapy may be supported by standard clinical laboratory results from commercially available assays or instrumentation supporting the eradication of the symptoms defining sepsis. The method of the invention may be practiced by continuously or intermittently administering a therapeutically effective dose of the inhibitor. The administration can be conducted for up to a total of about 60 days with a preferred course of therapy lasting for up to 10 days.
The decision to end therapy by the method of the invention may be supported by standard clinical laboratory results from commercially available assays or instrumentation or the disappearance of clinical symptoms characteristic of sepsis. The therapy may be restarted upon the return of sepsis. Pediatric forms of sepsis are also successfully treated by the methods, compounds, and formulations of this invention.
When the compound of the present invention is a crystallized, it may show various crystal forms and crystal habits.